Covalent modifications

On the other hand, and as discussed before, the chemical reactivity of CNT sidewalls increases vhth the tube curvature (i.e. decrease of the tube diameter), due to the increase of the pyramidalization angle and greater strain energy per atom [37,38]. Such pyramidalization of the CNT atoms causes the exohedral lobes of the orbitals to be larger than their endohedral counterparts. The reactivity of the surface is thus enhanced by the pronounced exposure of the hybrid orbitals from the exterior, which favors the orbital overlap vhth incoming reactants [38]. 

Accordingly, many reactions can be performed on the sidewalls of the CNTs, such as halogenation, hydrogenation, radical, electrophilic and nucleophilic additions, and so on [25, 37, 39, 42-44]. Exhaustively explored examples are the nitrene cycloaddition, the 1,3-dipolar cycloaddition reaction (with azomethinylides), radical additions using diazonium salts or radical addition of aromatic/phenyl primary amines. The aryl diazonium reduction can be performed by electrochemical means by forming a phenyl radical (by the extrusion of N2) that couples to a double bond [44]. Similarly, electrochemical oxidation of aromatic or aliphatic primary amines yields an amine radical that can be added to the double bond on the carbon surface. The direct covalent attachment of functional moieties to the sidewalls strongly enhances the solubility of the nanotubes in solvents and can also be tailored for different 

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Sefton, B., and Buss, J. E., 1987. The covalent modification of eukaryotic proteins widi Journal of Cell Biology 104 1449-1453. 

FIGURE 15.2 Enzymes regulated by covalent modification are called interconvertible enzymes. The enzymes protein kinase and protein phosphatase, in the example shown here) catalyzing the conversion of the interconvertible enzyme between its two forms are called converter enzymes. In this example, the free enzyme form is catalytically active, whereas the phosphoryl-enzyme form represents an inactive state. The —OH on the interconvertible enzyme represents an —OH group on a specific amino acid side chain in the protein (for example, a particular Ser residue) capable of accepting the phosphoryl group. 

Glycogen Phosphorylase Allosteric Regulation and Covalent Modification 473... 

FIGURE 15.17 The mechanism of covalent modification and allosteric regnlation of glycogen phosphorylase. The T states are bine and the R states bine-green. 

Pyruvate kinase possesses allosteric sites for numerous effectors. It is activated by AMP and fructose-1,6-bisphosphate and inhibited by ATP, acetyl-CoA, and alanine. (Note that alanine is the a-amino acid counterpart of the a-keto acid, pyruvate.) Furthermore, liver pyruvate kinase is regulated by covalent modification. Flormones such as glucagon activate a cAMP-dependent protein kinase, which transfers a phosphoryl group from ATP to the enzyme. The phos-phorylated form of pyruvate kinase is more strongly inhibited by ATP and alanine and has a higher for PEP, so that, in the presence of physiological levels of PEP, the enzyme is inactive. Then PEP is used as a substrate for glucose synthesis in the pathway (to be described in Chapter 23), instead... 

The serine residue of isocitrate dehydrogenase that is phos-phorylated by protein kinase lies within the active site of the enzyme. This situation contrasts with most other examples of covalent modification by protein phosphorylation, where the phosphorylation occurs at a site remote from the active site. What direct effect do you think such active-site phosphorylation might have on the catalytic activity of isocitrate dehydrogenase (See Barford, D., 1991. Molecular mechanisms for the control of enzymic activity by protein phosphorylation. Bioehimiea et Biophysiea Acta 1133 55-62.)... 

FIGURE 25.29 (a) The structures of several commou analgesic agents. Acetaminophen is marketed under the tradename Tylenol. Ibuprofen is sold as Motrin, Nuprin, and Advil, (b) Acetylsalicylate (aspirin) inhibits the cyclooxygenase activity of endoperoxide synthase via acetylation (covalent modification) of Ser ... 

An alternative approach to asymmetric synthesis that avoids covalent modification of the substrate is chiral modification of the active reagent. This not only streamlines the number of synthetic manipulations, but it simplifies the isolation of the desired product. In the case of zinc carbenoids, such modifications are feasible alternatives to the use of a standard chiral auxiliary. Two important factors combine... 

Benznidazole, a nitroimidazole derivative, has a mode of action that seems to involve covalent modification of macromolecules by nitroreduction intermediates. 

Histone acetylation is a reversible and covalent modification of histone proteins introduced at the e-amino groups of lysine residues. Histones and DNA form a complex - chromatin - which condenses DNA and controls gene activity. Current models interpret histone acetylation as a means to regulate chromatin activity. 

Evolution has provided the cell with a repertoire of 20 amino acids to build proteins. The diversity of amino acid side chain properties is enormous, yet many additional functional groups have been selectively chosen to be covalently attached to side chains and this further increases the unique properties of proteins. Diese additional groups play a regulatory role allowing the cell to respond to changing cellular conditions and events. Known covalent modifications of proteins now include phosphorylation, methylation, acetylation, ubi-quitylation, hydroxylation, uridylylation and glycosyl-ation, among many others. Intense study in this field has shown the addition of a phosphate moiety to a protein... 

In mammalian cells, the two most common forms of covalent modification are partial proteolysis and ph osphorylation. Because cells lack the ability to reunite the two portions of a protein produced by hydrolysis of a peptide bond, proteolysis constitutes an irreversible modification. By contrast, phosphorylation is a reversible modification process. The phosphorylation of proteins on seryl, threonyl, or tyrosyl residues, catalyzed by protein kinases, is thermodynamically spontaneous. Equally spontaneous is the hydrolytic removal of these phosphoryl groups by enzymes called protein phosphatases. 

REVERSIBLE COVALENT MODIFICATION REGULATES KEY MAMMALIAN ENZYMES... 

Mammalian proteins are the targets of a wide range of covalent modification processes. Modifications such as glycosylation, hydroxylation, and fatty acid acylation introduce new structural features into newly synthesized proteins that tend to persist for the lifetime of the protein. Among the covalent modifications that regulate protein function (eg, methylation, adenylylation), the most common by far is phosphorylation-dephos-phorylation. Protein kinases phosphorylate proteins by... 

Figure 9-7. Covalent modification of a regulated enzyme by phosphorylation-dephosphorylation of a seryl residue.

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